Cell and gene therapy is reshaping oncology, with chimeric antigen receptor (CAR) T-cell therapies delivering strong results in blood cancers while facing persistent access, manufacturing and real-world performance challenges.
Ex vivo CAR T has proven efficacy in B-cell leukemias and lymphomas and several products are FDA approved. Commercialized therapies are moving into earlier lines of care, and next-generation programs include off-the-shelf allogeneic products and dual-target CARs (for example CD19/CD20 or CD19/CD22) designed to reduce relapse from antigen escape. Clinical data suggest dual-target approaches may extend remissions, but efficacy in solid tumors remains limited because of suppressive tumor microenvironments. Strategies such as combining CAR T with checkpoint inhibitors and engineering chemokine receptors to improve tumor infiltration are under investigation.
As approved CAR T options expand, new ex vivo trials face a higher evidentiary bar. Sponsors must plan comparator strategies that reflect regulatory and payer expectations, prioritizing randomized head-to-head or add-on designs where feasible and using rigorously constructed external control arms with high-quality real-world data when direct comparison is impractical. Global trial footprints should account for regional differences in CAR T availability to avoid enrollment and ethical challenges.
Trial endpoints must go beyond response rate and progression-free survival to include measures such as minimal residual disease negativity, time to next treatment and patient-reported outcomes to satisfy health technology assessments. Transparent manufacturing metrics—vein-to-vein time, product success rates, bridging therapy exposure and expanded access for out-of-spec products—are increasingly required by regulators and payers. Early integration of commercial access planning into trial design is essential.
In vivo CAR T technologies aim to engineer CARs inside the patient, removing the need for leukapheresis and ex vivo manufacturing. Two platforms have entered first-in-human testing: engineered viral vectors (lentiviral or gamma-retroviral) that aim for durable, genome-integrated CAR expression, and targeted RNA–lipid nanoparticle (LNP) systems that deliver RNA encoding CAR constructs for transient expression and potential re-dosing.
In vivo approaches offer operational scalability, broader site eligibility and the potential to reach frail patients who cannot tolerate lymphodepletion. Early data in B-cell malignancies are encouraging, but each platform brings distinct safety and regulatory considerations. Viral vectors require long-term monitoring for insertional mutagenesis under FDA gene therapy guidance. RNA-LNP systems avoid genomic integration but raise concerns about LNP toxicity, immunogenicity and hypersensitivity in addition to standard CAR T risks such as cytokine release syndrome and neurotoxicity. Determining the persistence needed for durable remissions is a key unknown for transient-expression platforms.
Early-phase in vivo trials resemble conventional drug studies and can enable faster enrollment, but they must be designed to capture unique pharmacology and safety signals. Recommended elements include translational biomarkers (circulating CAR T cells, circulating tumor DNA), robust safety monitoring tailored to the platform, clear dose and schedule strategies for RNA therapeutics, and site selection that balances broader access with the capability to manage CAR T-specific toxicities for initial cohorts. Adaptive trial designs and extended follow-up protocols help address small populations, evolving endpoints and the need for long-term safety data.
Regulators will require rigorous biodistribution studies to confirm vector targeting and minimize off-target effects, along with strict Chemistry, Manufacturing and Controls to ensure vector consistency and potency. These demands are especially important when evaluating RNA-based in vivo CAR platforms in healthy volunteers or non-oncology indications.
Both ex vivo and in vivo CAR T programs are pushing into solid tumors, combination regimens and non-malignant B-cell diseases. Ex vivo efforts are testing armored CARs and checkpoint inhibitor combinations, while in vivo approaches are exploring multi-receptor CARs and localized delivery to overcome tumor microenvironments. Success will depend on robust comparator designs and endpoints that clearly demonstrate clinical differentiation.
If validated, in vivo CAR T could reduce cost and complexity and broaden global access to CAR T therapies. However, novel safety, biodistribution and regulatory challenges must be addressed through careful trial design, comprehensive monitoring and early engagement with regulators and payers. Clinical trials will remain central to evaluating safety, efficacy and real-world applicability as CAR T technologies evolve.
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